Unmodified polysaccharides can have undesirable biological properties, such as rapid clearance from circulation, rapid degradation, and/or allergenicity. Two polysaccharides that are commonly employed in pharmaceutical compositions and therapeutic methods include starch and dextran.
Starch is a naturally occurring, highly biocompatible polymer. When starch is introduced into the bloodstream, it is rapidly digested by amylase. The fragments of the digested product are rapidly cleared from the vascular compartment through glomerular filtration and/or metabolism. For this reason hydroxyethyl starch (rather than starch) has been used as a long lasting plasma volume expander for several clinical indications. The hydroxyethylation of the starch molecule serves to slow the rate of digestion/excretion of the polymer.
Hydroxyethylation of starch using ethylene oxide or 2-chloroethanol has been common practice for production of colloidal plasma volume expanders. These processes have numerous disadvantages including employing highly toxic ethylene oxide, difficulty in controlling the extent of hydroxyethylation, inability to select among starch hydroxyl groups, toxic by products, and high cost. For example, hydroxyethylation with ethylene oxide occurs at any hydroxylic site, including sites that have already been hydroxyethylated, and with solvent, residual water, and impurities or side products in the reaction mixture. Lack of selectivity among sites on the starch molecule requires extensive hydroxyethylation of the starch, although modification of certain specific sites offers a greater degree of protection from enzymatic degradation.
Dextran has been used for a variety of pharmaceutical and therapeutic preparations over the past 40-50 years. The wide use of dextrans has included purified native dextrans for plasma replacement/volume expansion, dextran-active conjugates, iron-dextran iron supplements, and dextran coated particles for MRI contrast agents. For the most part dextran in a highly purified form is well tolerated by most of the patient population. However severe anaphylactoid responses are known to occur, and are in some cases severe enough to result in death.
In patients undergoing hemodialysis, iron deficiency is a common problem. Oral iron is frequently tried first, but because of poor patient compliance and discouraging side effects, it often fails to correct iron deficiency. Thus, clinicians often turn to parenteral iron. However, parenteral iron products are not without drawbacks.
Until quite recently, parenteral iron meant an iron-dextran product. Yet, iron-dextran products often cause life-threatening anaphylactic reactions. Alternatives to iron-dextran include complexes of sodium ferric gluconate sucrose and iron sucrose. While these alternative complexes often solve the problem of anaphylactic reactions, such complexes have their own undesirable side effects.
Ferric gluconate causes transient hypotension and flushing in 1% of exposed patients and can reoccur on re-exposure. In addition, an interaction with ACE inhibitors leading to erythema, nausea, vomiting, cramps, and/or hypotension has been reported. Finally, rapid release of iron from the ferrous gluconate complex can lead to circulating free iron, with resultant oxidative stress or other possible ill effects, especially if too much iron is given at once.
In contrast, iron sucrose appears to have a reduced side-effect profile. However, as with iron gluconate, too rapid administration of too much iron sucrose, especially in the patient with a low iron-binding capacity, might lead to iron oversaturation, with circulating free iron and the potential for adverse effects. Thus, like iron gluconate, iron sucrose is best given in several small doses and not in a single total-dose infusion.
These undesirable properties of polysaccharides employed in pharmaceutical compositions and therapeutic methods indicates the need for modified polysaccharides, such as modified starches and modified dextrans, that have more desirable biological properties than the native or unmodified polysaccharides.
The present invention relates to modified polysaccharides that have more desirable biological properties than the native or unmodified polysaccharides, pharmaceutical compositions including these modified polysaccharides, methods employing these modified polysaccharides, and methods of reducing the undesirable biological properties of these modified polysaccharides. Preferably, the modified polysaccharide is an oxidized and reduced polysaccharide. Preferably the polysaccharide is reduced with periodate. In a pharmaceutical composition, the oxidized and reduced polysaccharide can be formulated in a pharmaceutically acceptable vehicle.
Preferred polysaccharides for modification according to the present invention include starch and/or dextran. An oxidized and reduced starch preferably exhibits a longer vascular half-life than unmodified starch, slower degradation by amylase than unmodified starch, and/or slower clearance from an animal than unmodified starch. An oxidized and reduced soluble dextran preferably exhibits reduced allergenicity compared to dextran. Preferably, the greater the extent of oxidation of the polysaccharide, the polysaccharide exhibits a longer the vascular half-life, slower degradation, slower clearance, and/or less allergenicity.
The modified polysaccharide can be a component of or be employed to form a conjugate, such as a conjugate with a chelator. A preferred chelator is deferoxamine (DFO). The modified polysaccharide can also be used to make pharmaceutical compositions by complexing it with micro-crystalline iron for parenteral administration.
A method of the invention includes increasing the vascular half life of starch by oxidizing and reducing the starch, and administering the oxidized and reduced starch into the circulation of a mammal. In another embodiment, the method of the invention includes decreasing the allergenicity of dextran by oxidizing and reducing the dextran, and administering the oxidized and reduced dextran into the circulation of a mammal. The dextran or starch administered can include a conjugate or a complex of the polysaccharide with iron.